Mice with the targeted (knockout, KO) mutation of the gene for low affinity p75 neurotrophin receptor have been generated (Lee et al., 1992, 1994a,b); and they have sparse nociceptive cutaneous nerve fibers, reduced heat/pain sensitivity, and depletion of some sympathetic innervation in young and old mice. The older adults also have defective hair and toenail formation and skin ulceration. Preliminary immuno- cytochemical studies of dental tissue in these mice show increased sensory innervation of molar teeth in old (5-6 month) adults with the p75 mutation; and the old mice have progressive deformation of dental and periodontal tissue. The proposed studies will use immunocytochemistry to define the extent and onset of dental deformations as well as the cytochemistry and distribution of dental innervation in molars of young and old KO mice compared to normal litter mates. The expression of neurotrophins and their receptors in molar pulp will be studied by in situ hybridization in the same mice. Retrograde axonal transport of nerve growth factor in mandibular nerve will be analyzed. Finally, the reactions of molar pulp and nerves to two specific types of dental injury (shallow cavity or pulp exposure) will be compared in the young adult KO and control mice using immunocytochemistry and in situ hybridization; and reactions in trigeminal ganglia to pulpitis induced by pulp exposure will be assessed. These studies will allow direct tests of the function(s) of the p75 neurotrophin receptor for dental tissue formation, dental innervation and neuro-inflammatory reactions to tooth injury. They are the first part of a larger plan to use a variety of mutant mice to study relationships between tissue reactions, inflammation and nociceptive sensory nerves in normal and inflamed dental tissue. Previous work has established that dental injuries in rats are an excellent system for correlating tissue and neural reactions during peripheral injury, inflammation and wound healing with responses in sensory ganglia and central nervous system (Byers et al., 1990a,b,c). The proposed work will extend this paradigm to the mouse so that questions about mechanisms during neruo-inflammatory reactions and wound healing can be tested in mice with specific mutations.